Placebo-controlled phase 2 trials

Placebo-controlled phase 2 trials

Have we lost equipoise? Is it unethical to randomise people with MS to a placebo-controlled phase 2 proof-of-concept trial?

The ethics of placebo-controlled phase 3 disease-modifying therapy (DMT) trials in multiple sclerosis (MS) are well-rehearsed; most ethics committees don’t approve these studies. However, in countries with limited access to licensed therapies due to economic constraints, placebo-controlled trials are still being conducted. Participating in a trial, albeit placebo-controlled, is one way of accessing a potential DMT.  

An example of this is the current vidofludimus phase 3 studies. 

Studies to Evaluate the Efficacy, Safety and Tolerability of IMU-838 in Patients With Relapsing Multiple Sclerosis (ENSURE-1 & 2). ( ID NCT05134441NCT05201638)

Despite my enthusiasm for the drug, based on its modes of action, it would not be possible to recruit patients to this study in our centre as it is placebo-controlled. We said no because we thought it was unethical. Maybe we were wrong? 

Vidofludimus is a new-generation dihydroorotate dehydrogenase inhibitor (DHODHI), which is much better tolerated than teriflunomide. It has potent antiviral effects, including targeting EBV, hence my interest in the drug. It is much cleaner than teriflunomide. Hence, it is very well tolerated and with few side effects. More recently, it has also been shown that vidofludimus acts as a potent nuclear receptor-related 1 (Nurr1) activator. Nurr1 is a neuroprotective transcription factor and an emerging target in neurodegenerative diseases. Activation of Nurr1 is likely to be responsible for the drug’s neuroprotective effects. It may explain its potential impact on smouldering MS. 

Vidofludimus reduces MS-related fatigue, possibly due to its anti-EBV activity, and significantly lowers serum neurofilament levels in progressive MS. These data were presented at the recent ACTRIMS meeting. 

It is an exciting time for MS, and if vidofludimus is shown to be the first DMT to target smouldering MS, it would have reached patients against the odds. It has also made me question the assumption that placebo-controlled trials are unethical. I am aware that pwMS have the option of deciding not to be treated with DMTs, and many opt for no treatment. Given its novelty as a DMT, is it not patronising for us HCPs not to offer pwMS the option of participating in a placebo-controlled trial of vidofludimus? 

Phase 2 placebo-controlled trials

The ethical arguments against placebo-controlled trials are now moving to phase 2 studies. Some HCPs now feel placebo-controlled phase 2 studies are unethical. This is a problem. If we can’t do proof-of-concept phase 2 trials, then MS drug development will stop. Doing phase 2 trials against an active comparator makes if virtually impossible to do proof-of-concept studies. Particularly as most licensed DMTs, which would be the active comparator, may impact the biology you are trying to study. 

For example, I am working on several proof-of-concept anti-EBV phase 2 trial designs. As most licensed DMTs impact memory B-cells, where EBV resides, comparing a new anti-EBV strategy to an active comparator would make it difficult to know if the drug is working. If we don’t compare new emerging agents to placebo, how will we know if the therapy in question impacts EBV and/or MS biology? 


Have we lost equipoise in relation to phase 2 placebo-controlled trials? 

People with MS and the ethics committees may have a different take on this dilemma than HCPs. Equipoise is about transparency and putting in place procedures to protect study subjects from unnecessary harm. With placebo-controlled trials, you could potentially have more subjects randomised to the active treatment than placebo, say, a two-to-one ratio to give study volunteers a greater chance of accessing the potentially effective therapy. You could also include an escape clause so that when a study subject reaches the end-point, i.e. has a relapse or shows multiple new lesions on MRI; they can either come out of the study or be switched to open-label treatment with the new agent. Another option is to reduce the exposure from 6 months, the current standard, to 3 months. Three months is a relatively short period. In many healthcare settings, three months is the time pwMS have to wait to start a DMT because of administrative inertia and waiting times for infusion slots. 

Using more sensitive outcome measures may also reduce the number of study subjects exposed to a placebo. At present, we tend to base our decisions on the effect of the DMT on Gd-enhancing or new T2 lesions. In the future, using blood neurofilament levels as a more sensitive marker will allow us to test new therapies using fewer subjects. 

We must not forget that a rich-world worldview doesn’t address the reality on the ground. In many countries, many pwMS can’t afford DMTs or are uninsured. Therefore, participating in clinical trials allows them access to potential DMTs. It is well known that subjects with MS who participate in clinical trials do better than pwMS managed outside clinical trials. The latter observation is probably based on patients' overall better care in clinical trials. Should we deny these people access to a potential treatment because people in high-income countries with universal healthcare systems think randomising them to a placebo is unethical? 

Let's have a wider discussion and explore some of the options above with pwMS, organisations representing pwMS, statisticians, ethicists, ethics committees and the wider MS community before we take the moral high ground that placebo-controlled phase 2 MS trials are unethical. 

I need your help with a short (1 minute) survey. Have we lost equipoise? Is it unethical to randomise pwMS to a placebo-controlled phase 2 proof-of-concept trial? Please remember a lot is riding on this issue. If we start saying no to placebo-controlled phase 2 trials, developing the next generation of MS DMTs will become very difficult. 

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Please note that the opinions expressed here are those of Professor Giovannoni and do not necessarily reflect the positions of Queen Mary University of London or Barts Health NHS Trust. The advice is intended as general and should not be interpreted as personal clinical advice. If you have problems, please tell your healthcare professional, who will be able to help you.

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